Huang Ye-Wei, Wang Li-Tian, Zhang Meng, Nie Yan, Yang Jin-Bo, Meng Wen-Luer, Wang Xuan-Jun, Sheng Jun
Key Laboratory of Pu-er Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming, 650201, China.
College of Science, Yunnan Agricultural University, Kunming, 650201, China.
Food Funct. 2023 Apr 3;14(7):3269-3278. doi: 10.1039/d2fo02701a.
Increasing low-density lipoprotein receptor (LDLR) protein levels represents a key strategy for the prevention and treatment. Berberine can reportedly alleviate non-alcoholic fatty liver disease (NAFLD) by increasing the LDLR expression in an ERK1/2 signaling-dependent manner of NAFLD. Studies have shown that caffeine can inhibit fat deposition in the livers of mice; however, caffeine has not been reported to alleviate NAFLD by augmenting the LDLR expression targeting EGFR. Here, an MTT assay, western blotting, RT-qPCR, immunohistochemistry, and surface plasmon resonance (SPR) analysis were used to investigate the role of caffeine in low-density lipoprotein cholesterol (LDL-C) clearance both and . , we found that caffeine could activate the EGFR-ERK1/2 signaling pathway in HepG2 cells, leading to increased LDLR mRNA and protein expression, and this effect could be inhibited by cetuximab. The SPR assay results have indicated that caffeine may increase the LDLR expression by directly binding to the EGFR extracellular domain and activating the EGFR-ERK1/2 signaling pathway. , caffeine markedly improved fatty liver and related blood indices in ApoE KO mice with high-fat-diet-induced NAFLD. Consistent with our results, we found that caffeine could also activate EGFR-ERK1/2 signaling and promote the LDLR expression in ApoE KO mice. In summary, caffeine can enhance the LDLR expression by directly binding to EGFR and activating the EGFR-ERK1/2 signaling pathway. EGFR signaling may represent a novel target for the prevention and treatment of NAFLD.
提高低密度脂蛋白受体（LDLR）蛋白水平是预防和治疗的关键策略。据报道，小檗碱可通过以非酒精性脂肪性肝病（NAFLD）的ERK1/2信号依赖性方式增加LDLR表达来缓解NAFLD。研究表明，咖啡因可抑制小鼠肝脏中的脂肪沉积；然而，尚未有报道称咖啡因可通过增强靶向表皮生长因子受体（EGFR）的LDLR表达来缓解NAFLD。在此，采用MTT法、蛋白质印迹法、逆转录定量聚合酶链反应（RT-qPCR）、免疫组织化学和表面等离子体共振（SPR）分析来研究咖啡因在低密度脂蛋白胆固醇（LDL-C）清除中的作用。我们发现，咖啡因可激活HepG2细胞中的EGFR-ERK1/2信号通路，导致LDLR mRNA和蛋白表达增加，且这种作用可被西妥昔单抗抑制。SPR分析结果表明，咖啡因可能通过直接结合EGFR胞外域并激活EGFR-ERK1/2信号通路来增加LDLR表达。此外，咖啡因显著改善了高脂饮食诱导的NAFLD的载脂蛋白E基因敲除（ApoE KO）小鼠的脂肪肝和相关血液指标。与我们的体外结果一致，我们发现咖啡因还可激活ApoE KO小鼠中的EGFR-ERK1/2信号并促进LDLR表达。总之，咖啡因可通过直接结合EGFR并激活EGFR-ERK1/2信号通路来增强LDLR表达。EGFR信号可能是预防和治疗NAFLD的新靶点。
